This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The availability of agents from new and existing ARV classes will improve the ability to achieve virologic suppression in triple class-experienced patients. The Department of Health and Human Services (DHHS) treatment guidelines recommend using at least two agents that are likely to be active in heavily treatment-experienced patients because HIV drug resistance will develop quickly if only one active agent is added to a failing regimen. Using another active agent such as ENF with TPV or DRV significantly increased the rate of virologic success (<50 copies/mL) for patients in both RESIST and POWER studies. In the POWER 3 (DRV) study, 30% of the patients who received DRV had prior experience with TPV, were using TPV at screening, or showed no baseline sensitivity to TPV. All three groups responded to treatment with DRV. Additionally, more than half of the patients experiencing virologic failure on the approved dose of DRV in the POWER study remained susceptible to TPV suggesting that sequencing of these two PIs may be possible. Treatment-experienced patients with triple-class-resistant virus represent a heterogeneous group in terms of prior ARV history and ARV susceptibilities. Given the preliminary results of treatment with TPV, DRV, MVC, or RAL demonstrating that improved virologic suppression is possible even in patients with extensive prior ARV exposure and/or HIV drug resistance, the achievement of plasma HIV-1 RNA levels below 50 copies/mL in more than 50% of patients may represent a new goal of therapy for these treatment-experienced patients. Given this emerging expectation and the heterogeneity of the treatment-experienced population, randomization to fixed regimens or to OBR with or without one new agent is not a desirable strategy. Furthermore, selection of any regimen in this population should be based on informed interpretation of the HIV resistance and HIV-1 co-receptor tropism assay results. This requires careful selection of a new regimen, based upon consideration of partially and fully active agents. According to DHHS Guidelines, a new regimen for the highly treatment-experienced patient should ideally include two or more fully active agents. However, the number of active agents needed for a high rate of virologic success and the role of recycled agents with unknown potential activity are both unclear. Furthermore, the value of keeping NRTIs in the combined ARV regimen is uncertain due to the likelihood that within-class HIV resistance and cross resistance has developed over time. For many triple class experienced patients, drug resistance will have developed to all NRTIs and selection of an active NRTI is not possible. One possible exception to this is the partial activity of lamivudine in patients harboring virus with the lamivudine resistance mutation (M184V). A 0.5 log10 decrease in viral load was seen with the use of lamivudine (3TC) in patients with M184V-containing virus. Whether this partial activity is needed in a highly active new regimen comprising at least two active agents is not known, but will be evaluated in A5241. Although NRTIs may contribute partial antiretroviral activity, the potential benefit must be balanced against their additional toxicity, cost, and total pill burden. Several studies have shown an increase in viral load in subjects with virologic failure when NRTIs are discontinued, suggesting a modest effect of NRTIs even in the face of resistance. However, a randomized trial continuing lamivudine versus discontinuing all antiretroviral medications (COLATE) did not confirm a benefit to continuing lamivudine. These observations highlight the importance of addressing whether the modest antiviral effects of NRTIs in subjects with NRTI-resistant virus justify their inclusion when a regimen of new agents with a cPSS >2.0 can be constructed. Achieving virologic suppression remains the goal for all patients starting or changing therapy. The availability of multiple new agents with activity against resistant virus may actually change the treatment paradigm for heavily ARV-experienced patients from one that emphasizes maintenance of immunologic function to one that expects a high likelihood of achieving suppression of plasma HIV-1 RNA to <50 copies/mL. The availability of multiple new agents allows one to consider changing the paradigm of always including NRTIs in treating three class-resistant virus. Whereas previous studies in this population were considered a success if 50% of patients had plasma HIV-1 RNA of <50 copies/mL at 24 weeks, A5241 will evaluate whether 75% of subjects can achieve this virologic goal at 48 weeks using multiple new agents with or without NRTIs. Therefore, we propose a strategy study in which an active drug regimen is selected from a panel of agents based on a subject s history and drug susceptibility tests, with the goal of achieving plasma HIV-1 RNA <50 copies/mL in 75% of subjects at study week 48. Furthermore, we propose using the cPSS to build an acceptable regimen with at least two active agents and then randomize subjects to add or omit NRTIs. Specifically, a subject s cPSS would be the sum of the scores given to agents within a potential regimen, as determined by genotype/phenotype resistance and tropism testing, with fractional scores between 0 and 1 given for drugs in the panel with evidence of partial activity. While the cPSS has been retrospectively identified as an important predictive factor in determining virologic success or failure n other studies in treatment-experienced populations, A5241 proposes to be one of the first to use the cPSS in a prospective fashion. Thus, A5241 proposes to prospectively evaluate the virologic benefit and toxicity of adding NRTIs to a treatment regimen selected to have a cPSS of >2.0 versus not adding NRTIs, in subjects with triple-class ARV experience and expected multiple drug cross resistance. Because safety and pharmacokinetic data are not available from patients younger than 16 years for investigational agents, the study will enroll subjects of at least 16 years of age.